PXD056483
PXD056483 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia |
| Description | LC-MS data and DIA-NN search files relating to: PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia. Abstract: The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularly the eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic. |
| HostingRepository | MassIVE |
| AnnounceDate | 2024-10-23 |
| AnnouncementXML | Submission_2024-10-23_03:30:10.072.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Adam Dowle |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Oxidation |
| Instrument | timsTOF HT |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2024-10-03 07:47:25 | ID requested | |
| ⏵ 1 | 2024-10-23 03:30:10 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: PU.1, Acute Lymphoblastic Leukemia, Glucocorticoids, Resistance |
Contact List
| Duohui Jing | |
|---|---|
| contact affiliation | Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai |
| contact email | jdh12262@rjh.com.cn |
| lab head | |
| Adam Dowle | |
| contact affiliation | University of York |
| contact email | adam.dowle@york.ac.uk |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/v08/MSV000096019/ |
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